Human immunodeficiency virus-2 (HIV-2) has been isolated from West Africans. When compared to HIV-1, the nucleotide sequence, in vitro properties, and clinical behavior of HIV-2 define it as a related but unique virus. HIV-1 is a cause of acquired immunodeficiency syndrome (AIDS), wasting, neurologic syndromes, and death in much of the world. HIV-2 may be less pathogenic. This is a proposal to study structural and functional properties of the envelope glycoproteins of HIV-2, answering questions important to the biology, pathogenesis, immunology, and therapy of all HIV infection. The particular emphasis on HIV-2 envelope glycoproteins and on HIV-induced syncytium formation in CD4-positive lymphocytes reflects: 1) the proposed major role of HIV-induced syncytia in lymphocyte depletion and subsequent AIDS; 2) the report of an isolate of HIV-2 which does not cause syncytium formation and which is comprised of a mixture of viruses with full-length and truncated transmembrane glycoproteins; and 3) preliminary reports of a reduced incidence of AIDS in West Africans infected with HIV-2 when compared to HIV-1 infected patients elsewhere. The specific objectives are to: 1) express the envelope gene of known and novel isolates of HIV-2 in eukaryotic cells using a recombinant vaccinia virus system; employ the recombinants in the experiments below; make polyclonal rabbit antisera to the recombinant HIV-2 glycoproteins; 2) study fusion activity of different HIV-2 isolates, also characterizing the pH optimum; host cell dependence of cleavage; effects of potential fusion inhibitors; and possible existence of a host cell fusion receptor distinct from the binding receptor; 3) predict, through deduced amino acid sequence comparison, the crucial molecular features in HIV-2 isolates observed to lack fusion, and test these predictions by site-directed mutagenesis studies; 4) study the biologic results of naturally occurring and experimental truncation of the transmembrane glycoprotein of HIV-2 specifically evaluating fusion, oligomerization, polarized expression, lateral mobility, and assembly into virions; and 5) develop conditions for large scale production and crystallization of HIV-2 envelope glycoproteins. The network of information and materials, the physical proximity of the laboratories of the investigators, and the complementary research projects encourage innovative collaboration in this PEBRA. As indicated in the proposal, this project will involve extensive collaborative efforts with other PEBRA investigators.